Alex De Nardi at PAGE 2026
Understanding how cells maintain protein homeostasis is a central challenge in neurodegenerative disease research. In Amyotrophic Lateral Sclerosis (ALS), mutations affecting selective autophagy pathways can impair the clearance of protein aggregates, contributing to neuronal dysfunction and disease progression.
At the Population Approach Group Europe (PAGE) Meeting 2026 in Dubrovnik, Croatia, COSBI PhD student Alex De Nardi presented the poster “A Minimal Mechanistic QSP-Ready Model to Bridge Aggrephagy and mTOR Signaling in ALS.”
The work focuses on the development of a mechanistic mathematical model of cellular proteostasis, describing the accumulation of ubiquitinated proteins and their clearance through proteasomal degradation and p62-dependent aggrephagy. The model places particular emphasis on p62/SQSTM1, a protein mutated in some ALS patients that plays a central role in both selective autophagy and mTOR signaling.
Using a system of ordinary differential equations calibrated with experimental data from the literature, the framework captures the interplay between aggrephagy and mTOR-related pathways under different cellular stress conditions. Model simulations revealed distinct qualitative behaviors, including stable healthy states, oscillatory dynamics and stress-induced transitions that may be relevant to disease progression.
The study provides a quantitative platform for investigating how ALS-associated mutations may affect autophagic flux and protein clearance mechanisms. More broadly, it lays the foundation for future Quantitative Systems Pharmacology (QSP) models that could support the identification and evaluation of therapeutic targets in ALS and other proteinopathies.
This work reflects COSBI’s ongoing efforts to integrate mechanistic modeling and systems biology approaches to better understand complex disease mechanisms and support model-informed therapeutic development.
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Digital copies of selected posters are available upon request at info@cosbi.eu.
